Malaria, a disease caused by protozoan parasites of the genus Plasmodium, is transmitted by the bite of Anopheles mosquitoes. Five species which cause disease in humans (P. falciparum, P. vivax, P. malariae, P. ovale and P. knowlesi) live and multiply first in hepatocytes (liver stage) then in red blood cells (blood stage). Each cycle of parasite multiplication lasts 48-72 hours and leads to the destruction of the host cell. It is manifested by symptoms like fever, headache, nausea, vomiting, diarrhea, prostration, chills. Left untreated, it may quickly develop into life-threatening complications such as cerebral malaria, severe anemia, acidosis, renal failure and pulmonary edema. There are other plasmodial species that infect hosts other than humans, such as P. berghei, that infects rodents.
Cerebral malaria, as defined by World Health Organization, is a clinical syndrome characterized by coma (inability to localize a painful stimulus) at least one hour after termination of a seizure or correction for hypoglycemia, detection of asexual forms of P. falciparum malaria parasites on peripheral blood smears and exclusion of other causes of encephalopathy. An unresolved issue of CM pathogenesis regards the role of brain hemodynamic perturbations and ischemia. Direct observation of retinal microvasculature shows impaired perfusion, vascular occlusion and ischemia (Beare, et al., J Infect Dis. 2009, 199, 263-271), whereas transcranial Doppler sonography shows normal or even increased cerebral blood flow (CBF) velocities in large arteries (Newton, et al., Pediatr Neurol. 1996, 1, 41-49).
Cerebral malaria (CM) caused by Plasmodium falciparum claims the lives of nearly 1 million children every year (Rowe, et al., Int. J. Epidemiol. 2006, 35, 691-704). Despite anti-malarial treatment, 10-20% of patients die and 1 in each 4 survivors develop neurological sequelae (McIntosh, et al., Cochrane Database Syst. Rev. 2000, 2, CD000527; John, et al. Pediatrics. 2008, 122, e92-99), therefore improved therapies are urgently needed.